9beta,11beta-oxido-16-methylene pregnene derivatives



9,8,11,8-XIDO-16-METHYLENE PREGNENE DERIVATIVES Eugene J. Agnello andGerald D. Laubach, Jackson Heights, N.Y., assignors to Chas. Pfizer &(30., Inc., New York, N.Y., a corporation of Delaware No Drawing.Application December 22, 1958 Serial No. 781,834

6 Claims. (Cl. 260-23955) sented by the formulas CH3 CH3 ('3H OR(IDHQORI CR 0 0 and the A A and A -derivatives of the 3,20-diketocompounds wherein R is an alkylenedioxy group containing from two tothree carbon atoms and R is hydrogen or an acyl hydrocarbon groupcontaining up to four carbon atoms.

As will be illustrated more fully hereinafter, these compounds areuseful for the preparation of therapeutically active compoundsrepresented by the formula ClJIEl'sOR and the A A and A -derivativesthereof wherein X is selected from the group consisting of hydrogen,halogen, 6

methoxy and ethoxy, Y is keto or fi-hydroxyl and R has the same meaningas above.

'A suitable starting compound for the preparation of zsoatsa PatentedSept. 1, 1959 ice the valuable compounds of this invention isrepresented by the formula This compound is prepared in accordance withthe procedure of Allen and Bernstein as reported in the Journal of theAmerican Chemical Society, vol. 7'8, page 1909.

The synthesis of the A -compounds within the purview of this inventionis illustrated by the following outline. The outline also shows the useof these compounds in the preparation of the valuable therapeutic agentsillustrated above.

In the first step of the synthesis of the valuable intermediates of thisinvention, the 16,21-diacetate prepared in accordance with Allensprocedure is dehydrated with methane sulfonyl chloride in pyridineaccording to known procedures illustrated in the appended examples toprepare a A -compound.

The 9,6,1lB-oxide is next prepared by treating the A -compound firstwith N-bromoacetamide and perchloric acid in peroxide free dioxane. Theresulting bromohydrin is treated with an alkaline reagent such aspotassium acetate to convert the bromohydrin to the oxide. Thisprocedure is fully illustrated in the appended examples.

I The 3,20-bis-diketal is next prepared. For this preparation thepreceding diacetate is first hydrolyzed, then converted to a diketal andthen reacetylated. These reactions are well known in the art and areillustrated in the appended examples.

Alkaline hydrolysis of the resulting diketals yields a 16,21-diol. Thisreaction is carried out using, for example, ,2 molar portions ofpotassium carbonate in aqueous methanol solution.

The '16,21-diol is next selectively acylated at the 21- position.Although other acylating agents can be used, it is preferred to use anequivalent of acetic anhydride in pyridine because of the readyavailability of these compounds and high yields which can be obtained bytheir use. Selective acylation at the 2l-position is a well known andsimple reaction which can be readily carried out without concurrentacylation of the other hydroxyl groups in the molecule.

Conversion of the 16a-ol-21-acetate to a 16-keto compound is readilyaccomplished with standard and well known oxidizing agents. It ispreferred to use the chromic acid-pyridine complex since the reactioncan be readily accomplished in high yields with minimum decomposition ofstarting material.

The 16-keto compound is next reacted with the Wittig reagent, that is,triphenylphosphine-methylene. The reaction is well known. Itsapplication to steroids is illustrated by Sondheimer and Mechoulam inthe Journal of the American Chemical Society, vol. 79, page 5029. The

application to-thepreparation of the valuable compounds of thisinvention is fully illustrated in the appended examples.

The 3,20-diketo-2l-acetate of the compound previously prepared is thenprepared by simultaneous hydrolysis of the ketal and acetate togetherwith formation of a 9,11-bromohydrin. This latter compound is con vertedto a 9,11-oxide and reacetylated in accordance with standard procedures.

A double bond at the 6(7)-position is introduced by treatment of theabove compound with a quinone having an oxidation-reduction potentialless than 0.5 at a temperature between 70 C. and 190 C. in an inertorganic solvent having a boiling point of atleastabout 70 C. Suitablesolvents include mononuclear aromatic hydrocarbons, mononuclearhalogenated aromatic hydrocarbons, oxygenated polar alicyclic organicsolvents and oxygenated polar aliphatic organic solvents. Typicalsolvents include tertiary butanol', n-amyl alcohol, hexanol, isoamylalcohol, heptanol, 3'-cyclohexanol, orthdichloro benzene, xylene,tertiary amyl alcohol, secondary amyl alcohol, benzene, toluene, aceticacid, propionic acid, butyric acid, butyl acetate, amyl acetate, hexylacetate, butyl propionate, propyl propionate, and amyl propionate. Theapplication of this reaction to the preparation of n -androstadiene9-halo compounds is illustrated. in US. Patent. No. 2,836,607, issuedJuly 27, 1958. Its application to the preparation of the specificcompounds of this invention is illustrated in the examples.

A double. bond. is introduced at the 1(2)-position of the precedingcompound by contacting it with selenium dioxide-in an inert organicsolvent at an elevated temperature. Solvents which are useful for thisreaction include, for example, tertiary butanol, tertiary pentanol,benzene, ethylene. glycoldiethers such as dibutyl Cellosolve, dipropylether, ethylene glycol and various other glycol ethers, phenetole,xylene, dioxane and naphthalene. Preferred conditions include theaddition of a lower aliphatic acid particularly acetic acid to atertbutanol mixture. In carrying out the reaction, it. is generallypreferred'to utilizetemperatures of from about.

75 C. toabout 200 C. for from about 1 hour to about 100'hours. seleniumdioxide are, added during the reaction period. The application of thisreaction is fully illustratedin copending patent application Serial No.672,550, filed August 18, 1957. Its application. to the specificcompounds of this invention is fully illustrated in the appendedexamples.

The valuable compounds of this invention are used to produce therapeuticagents by opening the epoxide ring to produce a 9a-halo, methoxy orethoxy compound having an llfi-hydroxyl group. These reactions are.fully described by Fried et -a1." inthe Journal of the AmericanChemicalSociety, vol; 79, page 113.0. The application to the specificcompounds of. this invention arefully i1- lustrated in the appended:examples. The. compounds prepared" by'these' reactions aretherapeutically active.

If'desiredrthe llfi-hydroxyl group can be oxidized'to an" 1 l-keto groupand compounds having this modification at the ll-position are alsovaluable therapeutic agents.

This oxidation can be carried out .by any of a number of wellknown-procedures including oxidation with chromium trioxide, sodiumdichromate', N bromoa'cetamide and aluminum isopropox-ide or aluminumtert-butoxide in the" presence of a hydrogen acceptorsuch as acetone or.cyclohexanone inan inert organic solvent such as benzene, toluene orxylene. It'is preferred, however, to utilize the chromie acid-pyridine.complex as. the oxidizing agent since, as-indicated above, ,in'connection with the oxidation of the lda-hydroxyl group,.the yieldsobtained are excellent.

It will be' noted, that'the procedures described aboveproduce'compound's with either a halogen or an alkoxy group atthe9a-position. For the preparation of the Generally several molecularproportions of 4': compounds of this invention in which there is ahydrogen at the 9-position, a 9a-bromo compound prepared asdeescribedabove is used. The bromine is removed using zinc and acetic acid byreactions well known in the art. The procedure is illustrated in theappended examples.

The synthesis illustrated above produces A -compounds. Othertherapeutically active compounds, for example, the A the A and the A-compounds can be prepared by obvious modifications of this basicsynthesis. Thus, to prepare a A -compound, the 9fi,11}3- oxide ring isopened with the appropriate reagent without resort to dehydrogenationwith a quinone and selenium dioxide. For the preparation of the A-compound, the A' -compound. is treated with selenium dioxide only andfor the preparation of the A -compound, only a quinoneis used;

As will be recognized by. those skilled in the art, there aremodifications of this. basic procedure which can be applied withoutessentially departing from. the scopecf the invention, for example, in.the. preparation: of the A -compound selenium dioxide can be used beforethe application or the quinone reaction: As stated" above, otherdihydroxy compounds can beused to prepare the diketals.Esters:-0ther-.than acetates-cambeemployed and alkaline hydrolysisreagents other than potassium carbonate are useful.

Although many of the reactions described above are applicable tocompounds in which the 2l-posit-ioncarries-afree hydroxyl group,foroptimum results it is best thabth'e hydroxylgroup be acylated with anacyl'hydrocarbon group. containing up :tofour carbonatoms.

Since the 2:1-position. hydroxyl group is' the. onlyprimary alcoholgroup present in any of' the molecules whether starting materialintermediate or' product, it

may be readily esterified by standard methods. Although.

Fischer esterificat-ion: and transesterificationprocedures a may beemployed, in general, it is preferred'to form-the esters by treatmentwith an acylating agent such as an acyl halide or anhydride in thepresence of a tertiary base suclr as pyridine or dimethylaniline. Freealcohols are prepared from the corresponding: esters by gentlehydrolysis, fonexample, by treatment with dilute-potassium carbonate in;aqueous methanol.

The following examples are given solely for'the purpose of illustrationand are not to be construed as limitations of this invention, manyapparent variationsof which hare possible without departing from thespirit or scope thereof.

EXAMPLE I A -pregnadiener16o 1 7 a,21 -tri0l-3,20-dione 16,21-di-.acetate affixed' a; sealed stirrer, a droppingfunnel and a con-- denser.The condenser and dropping funnel-are pro tected with drying tubes. Themixer is cooled to -20 C. and a solution containing 4.6 ml. of methanesulfonyl chloride in five ml. of pyridine is added dropwise over aperiod of one hour with continued stirring. At the end of the hour,stirring' isstopped, the reaction mixture allowed to come to. roomtemperature and left standing for ten hours. At the end of: this period,the solution is added dropwise to 750ml. ofiicecold water with stirring.The desired product precipitates and is recovered by filtration. It isdried and recrystallized from ethyl acetate.

EXAMPLE II 9a-br0mmA4-pregnena-1 1-18,] 6a,] 76:,21-tetr0'l-3,20-di0ne16,21-diacetate e To asu'spension of 500mg, of the product prepared'in.the previous example in .25 ml; of" pure peroxide free dioxane and .4ml. of 5.46 N perchloric acid there is added in the dark at roomtemperature with stirring over a one hour period 114 mg. of solidN-bromoacetamide. At the end of 25 minutes, all of the starting materialdissolves and 2.5 ml. of sodium sulfite solution is added with stirring.A few grams of ice in 20 ml. of chloroform is added and the layersseparated. The organic layer is washed twice with water whilemaintaining the temperature at about 20 C. by the occasional addition ofice. The organic solution is concentrated in vacuo and acetone is added.The mixture is maintained at a temperature of about 5 C. until crystalsform and the desired product is recovered by filtration.

EXAMPLE III 919,1lfi-oxidmN-pregnene-l6a,]7e,21-triol-3,20-dione16,21-diacetate minutes. After cooling in an ice bath, 400 m1. of icewater is added with stirring and the desired product precipitates.Successive crops of the desired product may be obtained by concentratingthe mother liquor.

EXAMPLE IV 9,8,11,8-xid0-M-pregnene 16:1,] 70:,21 trial-3,20-dione3,2-0-diethylene ketal 16,21-diacetate The compound of the previousexample (2 g.) is hydrolyzed with aqueous 10% methanol according tostandard procedures. It is precipitated from icewater, filtered anddried. This product is mixed with 15 ml. of ethylene glycol and 30 ml.of benzene and a small amount of water removed by azeotropicdistillation. To the mixture there is added 50 mg. of p-toluene sulfonicacid monohydrate and the mixture refluxed and stirred for 20 hours withcontinuous removal of water. At the end of this period the solution iscooled and made basic by the ad dition of 5% aqueous sodium bicarbonate.The aqueous mixture is extracted with a 1:1 solution of benzene andether, the organic layer separated, dried over anhydrous sodium sulfateand filtered. The filtrate is evaporated in vacuo, reacetylated as inExample VI and the desired product obtained in pure form byrecrystallization from acetone-petroleum ether (boiling point 6466 C.)..

EXAMPLE V QBJIB-oxido-M-pregnene 16u,17a,21 trial-3,20-di0ne 3,20-diethylene ket al EXAMPLE VI QBJIB-oxido-M-pregnene 16uc,17nc,2]trial-3,20-tlione 3,20-diethylene ketal 21 -acetate A solutioncontaining 1 g. of the 16,2l-diol prepared as described in the previousexample in 25 ml. of pyridine containing a molar equivalent of aceticanhydride is allowed to stand at room temperature for 8 hours. Thedesired 2l-acetate is isolated in the conventional manner.

6 EXAMPLE VII 9a,]1,B-oxido-M-pregnene 170.,21 diol 3,16,20- trione3,20-diethylene ketal 21 -acetate To 15 ml. of pyridine maintained atabout 5 C. there is added 0.15 g. of chromic anhydride and the mixtureallowed to warm spontaneously to room temperature. To this solutionthere is added 2 g. of the product prepared as described in the previousexample in 20 ml. of pyridine and the mixture permitted to stand atabout 25 C. for 24 hours. The solution is extracted with ether, theether layer separated, washed twice with 5% aqueous hydrochloric acid at10 C. and then with water. The organic layer is dried over anhydroussodium sulfate, filtered and the desired product obtained by evaporationin vacuo.

EXAMPLE VIII 9 3,11 ,B-oxido J6 methylene-M-pregnene 171x21 diol-3,20-di0ne 3,20-diethylene ketal ZI-acetate A 1 N ethereal solution ofbutyl lithium (9 ml.) is added to a suspension of 3.6 g. ofmethyltriphenylphosphonium bromide (prepared from methyl bromide andtriphenylphosphine using the procedure described by Wittig in Ber., 87,1318 (1954)) in 50 cc. of ether with swirling under nitrogen. Themixture is shaken in a nitrogen atmosphere for 2 hours and 0.5equivalents of the product prepared in the previous example dissolved in75 cc. of ether is added. The mixture is shaken for 5 hours and leftstanding overnight. The ether is distilled off while simultaneouslyadding tetrahydrofuran until most of the other has been replaced withthis latter solvent. The mixture is refluxed for 6 hours, cooled,diluted with water and extracted with ether. The organic layer isseparated,

washed with water, 5 hydrochloric acid and again with water. It is driedover anhydrous sodium sulfate, filtered and the filtrate evaporated invacuo. The pure product is obtained by recrystallization from ethylacetate.

EXAMPLE IX 918,11}? oxia'o 16 methylene A pregnene17a,21-dial-3,20-dione 21 -acelate A mixture of 1 g. of the compound preparedin the previous example together with 20 ml. of 46% aqueous hydrobromicacid and an equal volume of chloroform is stirred vigorously at roomtemperature for 16 hours. The" EXAMPLE X 95,11 8-oxid0-16-methylene Apregnaditene :,21- dial-3,20-dione 21-acetate A mixture containing 1.3g. of the product prepared in the previous example and 3.0 g. ofchloranil in 30 ml. tert-butanol is refluxed in a nitrogen atmospherefor 18 hours. The reaction mixture is then diluted with 250 ml.

of chloroform. The solvent solution is washed with several smallportions of 5% sodium hydroxide solution and then with water. It isdried over anhydrous sodium sulfate, filtered and concentrated in vacuoto leave the desired product as a residue.

EXAMPLE XI 95,] 1 ,B-oxido-16-methylene A pregnatriene-17a,2]-dial-3,20-a'i0ne 21-acetate A mixture of 0.8 g. of the product preparedin the previous example, 0.8 g. of selenium dioxide (freshly sublimed)and 10 ml. of t-butyl alcohol is heated ma 9a l2r0m0 r hylenerA--pregnatriene-1.1 ;3,1.7u,.21- trial-3,20-dione 21acetate To a solutionof 250 mg. of the product prepared in the previousrexamplevin 51ml. ofglacial acetic .acid and 5 ml. of carbontetrachloridathere, is added0.4- ml..of 3.2% hydrobromic acid in acetic acid. After 10 minutesatroom temperature: 100ml. of chloroform is. added and the solution washedtwice with equal volumes of water. The organic layer isdried overanhydrous sodium sulfate; filtered and the desired product isolated byevaporating at reduced pressure.

EXAMPLE XIII Qua-chlqro 16 methylene-A -pregnatriene-l1/3,17oc,21- triol-3,-20-dione 21 -a,cetate ,A solution of'4 g. of the compoundprepared in Example XI in 40 ml. of redistilled chloroform is preparedand 3.5 ml. of 0.45- N hydrogenjchloride in chloroform solution is addedover a 20 minute period. ,The reaction mixture ismaintained-atpOf C. foran additional hour. The chloroform solution is washed with water,separated, dried over anhydrous sodium sulfate; filtered and, the

desired product isolated by evaporation of the solvent in vacuo EXAMPLEx v 9oc-iado 16 methylene-A -pregnatriene-ll (3,1Za,21- tril-3,20-di0neZI-acetate solution of v204 mg. of the compoundprepared in Example XI in20 r'nl..of chloroformiscooled to 20 C. and 0.4 ml. of 55% aqueoushydriodicacid ,is .added. The mixture is agitated for 20 minutes. Wateris added, ltheorganic llayer separatedand carefully evaporated in vacuoto leave av crystalline residue of the desired product which can bepurified by recrystallization from ethyl acetate. below 40C.

- EXAMPLE XV 9a-flu0r0 16 methylene-A -pregnatriene-1113,1 Z a,21-tri0l-3,20.-di0ne 21,-acetate Approximately 6 g. of anhydrous hydrogenfluoride is passed into a solution containing g. of the" compoundprepared in accordance-withthe procedure of Example X1 in 100ml. of.redistilled chloroformcat- 0 C. with constant stirring. The reaction.mixtureyis maintained at this temperature for .2 hours and then made.alkaline by. the careful addition ,of aqueoussodiurn bicarbonatesolution. The reactionmixture. .is extracted with chloroform, .the:organic .layer dried. over anhydrous sodium .sulfate,,filtered and thefiltrate evaporatedzttoleaveqthe .desiredproduct .as .a residue.

EXAMPLEXVI 9a-meth0xy-16-methylene-A -pregnatriene-l118,1 7a,21-trial-5,20-zii0ne 21 acetate A solution ofzthercompound prepared asdescribed in Example XI (5 g.) ,in 250 .ml. of methanol and 1.9,.ml. of,72% 'perchloric acid is. allowed to remain at room temperature for4.hours. V "The solutiongis neutralized with aqueous sodium bicarbonateandthernethanol removed in vacuo. ""T'hemixture is extracted withchloroform and the clrlloro'formevapmated under-reduced; pressure: to'provide the 'de'sired compound as-"the freefalcohobwhicli is convertedto *the corresponding acetate ;by acetyl'ationwith"'5"rnl.-ofactic"anhydride in an equal volurne bf pyridinefor"l5"-hours. The crystalline product isobtainedibyevaporationof thesolvent in-yacuo.

. EMM LE XVII Qwthoxy 1 6 -meth-ylefi@M-Q pregnatriane-I 1 (3,17 oil-1-'1ri0l-3,-2Q-dior e 21 ace-tare A solution of'the..componndpreparedusing'the ro edure described iriExample XI(5 g.) in 250 ml. of ethanoland 1.9 ml. of 72%. perchloricacid is allowed to remain at roomtemperature for "4' hours. The solution is neutralized with aqueous;sodium. bicarbonate. and ,the methanol removed in. vacuo. .The mixtureis extracted with chloroform and the chloroform evaporated under reducedpressure to; provide theadesired ."cornp ound= as tthe .free' 1 alcohol:which .--is .,=,conyerted to the corresponding acetate.byaacetylationvwith:5. ml.. of acetic .anhydride in.an.equall-=volume1of ;pyridine..for 15 hours. The crystallineproduct.is obtainedpby. .evgaporation of the-solvent in Macuo. a

The procedure ofExampleXI .-isa;applied identically .to the product.ofExample IX- to prepare 913,11/3-oxido-l6- methylene-.A -pregnadiene '117,21 diol-3',20+dione H21- acetate 1 and (this product is =treatedinaccordance withzthe procedures setaforth tin. Examples -XIIthroughFXWI .to prepare: 9a-bromo 16 methylene-A-pregnadiene-11fi,l7a,2l-

triol-3,20-dione .2 l-acetate 9oc-Chl0f0 '16 methylene-A-pregnadiene-1153170521- triol-3,20'-dione"21-acetate 90t-l0d0 16 methylene -1A pregnadiene-11p,17a,21-

, triol?3.,20 dione ZL-acetate 9u-flu0r0 -...16-- methylene-A"#pregnadiened1,8,17m2ltriol-3,2 0.-.dione.21-acetate 9,1xrmethoxy1-6.-methylene1A -pregnadiene-1 15,1 ,21-

triol'-3,20.-.dione 21 acetate 9a-ethoxy- 16 methyleneAwpregnadiene-l,113.17%21- trio1- ,ZOzdlQIlG 21racetate The procedures:of: Examples XII through were applliedtotheiproductof Example IXtoprepare. the .following. compounds.

9a-bromo 16 methyIeIIe-M -pregnene-I1B,17,21-triol- 3',20-dioneZI-acetate 9a-chloro 16 .methylene-A pregnene-l1fi,17a,21-triol-3,20-dione 21-acetate 9oc-i0d0 -i 16 methylene-Aft-pregnene11B,17a,21-triol- 3,20-dione Ill-acetate 9a-flu0r0 16methylene-M-pregnene-l1p,17u,21-triol 3,20-dione 2l-acetate 9a-methoxy16-methy1ene-A -pregnene-11fl,17a,2ltriol- 3,20-dione ZI-acetate9a-ethoxy 16 methylene-A -pregnene-11fi,17a,21-triol- 3,202di0fl6-21-acetate "The procedures of -Examples XII through 'XVII were appliedtothe product of Example Xto: prepare-the :following compounds.

9 EXAMPLE XVIII Chromic anhydride (0.125 g.) is added to 15 ml. ofpyridine at about C. and the mixture allowed to warm spontaneously toroom temperature. To this solution is added 25 g. of9a-bromo-16-methylene-A -pregnatri- CHE-1lfl,17u,21-t1'l01-3,20-dl01162l-acetate in 20 ml. of chloroform and the mixture allowed to stand atroom temperature for 24 hours. The solution is extracted with ether andthe organic layer washed twice with cold 5% aqueous hydrochloric acidand then with water. It is dried over anhydrous sodium sulfate, filteredand the desired product obtained by removal of the ether in vacuo.

The following compounds were prepared using the procedure of the aboveexample.

9a-chloro 16 methylene-A -pregnatriene 17a,2l

diol-3,11,20-trione 21 acetate 9oc-i0d0 16 methylene A -plregnatriene17a,21-

diol-3,ll,20-trione 21 acetate 9a-fluoro 16 methylene A -pregnatriene170;,21-

diol-3,1l,20-trione 21 acetate 9a-methoxy 16 methylene-A-p1regnatriene-17u,2l-

dial-3,1 1,20-trione 21 acetate 9a-ethoxy 16 methylene-A -pregnatriene170:,21-

diol-3,l1,20-trione 21 acetate 9a-bromo 16 methylene-A-pregnadiene-170:,2l-diol- 3,1 1,20-trione 21-acetate 9a-Ch1010 l6methylene-A -pregnadiene-17a,21-diol- 3,11,20-trione 21-acetate 9a-i0d016 methylene-A -pregnadiene-1711,21 diol- 3,11,20-trione Zl-acetate9a-fluoro 16 methylene-A -pregnadiene-l7a,2l-diol- 3,1 1,20-trione21-acetate 9a-methoxy l6-methylene-A -pregnadiene-170:,21-di0l-3,11,20-trione 21-acetate 9a-ethoxy 16 methylene-A-pregnadiene-l7a,21-diol- 3,1l,20-trione ZI-acetate 9a-bromo 16methylene-A -pregnene-17u,21-diol-3,11,

20-trione 2l-acetate 9ot-chloro 16 methylene-A-pregnene-17a,21-diol-3,11,

20-trione 21-acetate 9u-iodo 16 methylene-M-pregnene l7oc,21-diOl-3,1l,

20-trione 2l-acetate 9u-fil1010 16 methylene-A-pregnene-17u,21-diol-3,1l,

ZO-trione 2l-acetate 9a-methoxy 16-methylene-A-pregnene-17a,21-diol-3,ll,

20-trione 2l-acetate 9a-ethoxy 16 mEthYIEHB-A-PICgHBnB-I7a,2l-di0l-3,11,

20trione 21-acetate 9a-bromo 16 methylene-A -pregnadiene-l7a,21-diol-3,11,20-dione ZI-acetate 9a-chloro 16 methylene-A-pregnadiene-17a,21-diol- 3,11,20-dione 2l-acetate 9a-iodo 16methylene-A -pregnadiene 17a,21 diol- 3,11,20-dione 2l-acetate9oc-fillOI'O 16 methylene-A -pregnadiene-l7a,21-diol- 3,11,20-dione21-acetate 9a-methoxy 16-methylene-A -pregnadiene-17a,2l-diol-3,11,20-dione 21-acetate 9ot-ethoxy 16 methylene-A-pregnadiene-17a,21-diol- 3,11,20-dione 2l-acetate EXAMPLE XIX16-methylene-A -pregnatriene-I 7a,2]-di0l-3,1 1,20- trione 21-acetate Asolution containing 25 mg. of 9abromo-l6-methylene-A-pregnatriene-17a,21-diol-3,1 1,20-trione 2l-acetate in 2 ml. of glacialacetic acid is treated portionwise with 48 mg. of zinc dust on the steambath for a total of 15 minutes. The residual zinc was removed byconfiguration and the acetic acid solution evaporated to drya 16 ness invacuo. The residue was recrystallized from ace: tone to yield thedesired product in pure form.

This procedure was applied to other 9a-bromo-com-' pounds of this seriesto prepare corresponding A A and M' -compounds.

EXAMPLE XX 16-methylene-A -pregnatriene-II 5,1 7on2] -tri 0l 3,20-dione21-acetate A solution of 9a-bromo-1G-methylene-A -pregnatriene-I1,3,l7u,21-triol-3,20-dione 21-actate mg.) in a solution containing30 ml. of water and 5 ml. of alcohol was shaken with 1 g. of zinc dustat room temperature for 19 hours. The zinc dust is removed bycentrifugation and washed 'with alcohol. The alcohol solution isconcentrated in vacuo and the aqueous suspension extracted withchloroform. The residue from the chloroform extract is dissolved in 1:4chloroform and benzene and and chromatographed with silica gel (Davis-onNo. 923, 2 g.). Elution of the column with 1:1 chloroform and benzeneprovides the corresponding M -compound (identified by its infraredspectra). The fraction containing this compound is followed by furtherfractions which are isolated by evaporation of the solvent andrecrystallized from acetone to prepare the desired prodnet.

This procedure was applied to other 9a-bromo compounds of this series toprepare corresponding A A and A -compounds.

EXAMPLE XXI The free 21-alcohols of the esters prepared as in theprevious examples are each prepared by hydrolysis using an equivalent ofpotassium carbonate in 10% aqueous methanol solution. The mixture isallowed to stand at room temperature for one hour and then poured intoice water to precipitate the free alcohols.

EXAMPLE XXII A variety of 2l-esters of the compounds prepared inaccordance with the procedure of Examples XII through XX are eachprepared by treating each of the free alcohols of Example XXI withacylating agents by conventional methods. These include such compoundsas the formate, the propionate, the butyrate, the hexanoate, thebenzoate, the octanoate, the stearate, the eicosanoate, thehemisuccinate, the trimethyl acetate, the cyclohexylcarbonate, thecyclopentylpropionate, etc. The acid esters such as the hemisuccinatehave the advantagethat alkali metal and alkaline earth metal salts areprepared from them by treating with molar proportions of a base such assodium bicarbonate, potassium bicarbonate or calcium carbonate. Thesesalts, in addition to being biologically active are water soluble, anadvantage not possessed by the steroid alcohols themselves or byordinary esters thereof.

What is claimed is:

1. A compound selected from the group consisting of and the A A and A-derivatives of the 3,20-diketo compounds wherein R is an alkylenedioxygroup containing from two to three carbon atoms and R is selected

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF